Bone mineral density and chronic lung disease mortality: the Rotterdam study

Context: Low bone mineral density (BMD) has been associated with increased all-cause mortality. Cause-specific mortality studies have been controversial. Objective: The aim of the study was to investigate associations between BMD and all-cause mortality and in-depth cause-specific mortality. Design and Setting: We studied two cohorts from the prospective Rotterdam Study (RS), initiated in 1990 (RS-I) and 2000 (RS-II) with average follow-up of 17.1 (RS-I) and 10.2 (RS-II) years until January 2011. Baseline femoral neck BMD was analyzed in SD values. Deaths were classified according to International Classification of Diseases into seven groups: cardiovascular diseases, cancer, infections, external, dementia, chronic lung diseases, and other causes. Gender-stratified Cox and competing-risks models were adjusted for age, body mass index, and smoking. Participants: The study included 5779 subjects from RS-I and 2055 from RS-II. Main Outcome Measurements: We measured all-cause and cause-specific mortality. Results: A significant inverse association between BMD and all-cause mortality was found in males [expressed as hazard ratio (95% confidence interval)]: RS-I, 1.07 (1.01-1.13), P = .020; RS-II, 1.31 (1.12-1.55), P = .001); but it was not found in females: RS-I, 1.05 (0.99-1.11), P = .098; RS-II, 0.91 (0.74-1.12), P = .362. An inverse association with chronic lung disease mortality was found in males [RS-I, 1.75 (1.34-2.29), P < .001; RS-II, 2.15 (1.05-4.42), P = .037] and in RS-I in females [1.72 (1.16-2.57); P = .008], persisting after multiple adjustments and excluding prevalent chronic obstructive pulmonary disease. A positive association between BMD and cancer mortality was detected in females in RS-I [0.89 (0.80-0.99); P = .043]. No association was found with cardiovascular mortality. Conclusions: BMD is inversely associated with mortality. The strong association of BMD with chronic lung disease mortality is a novel finding that needs further analysis to clarify underlying mechanisms

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR &lt; 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.</p

Assessment of gene-by-sex interaction effect on bone mineral density

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.Medtronic NIH R01 AG18728 R01HL088119 R01AR046838 U01 HL084756 R01 AR43351 P01-HL45522 R01-MH-078111 R01-MH-083824 Nutrition and Obesity Research Center of Maryland P30DK072488 NIAMS/NIH F32AR059469 Instituto de Salud Carlos III-FIS (Spanish Health Ministry) PI 06/0034 PI08/0183 Canadian Institutes of Health Research (CIHR) NHLBI HHSN268201200036C N01-HC-85239 N01-HC-85079 N01-HC-85086 N01-HC-35129 N01 HC15103 N01 HC-55222 N01-HC-75150 N01-HC-45133 HL080295 HL087652 HL105756 NIA AG-023629 AG-15928 AG-20098 AG-027058 N01AG62101 N01AG62103 N01AG62106 1R01AG032098-01A1 National Center of Advancing Translational Technologies CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Diseases DK063491 EUROSPAN (European Special Populations Research Network) European Commission FP6 STRP grant 018947 LSHG-CT-2006-01947 Netherlands Organisation for Scientific Research Erasmus MC Centre for Medical Systems Biology (CMSB) Netherlands Brain Foundation (HersenStichting Nederland) US National Institute for Arthritis, Musculoskeletal and Skin Diseases National Institute on Aging R01 AR/AG41398 R01 AR050066 R21 AR056405 National Heart, Lung, and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc. N02-HL-6-4278 Canadian Institutes of Health Research from Institute of Aging 165446 Institute of Genetics 179433 Institute of Musculoskeletal health 221765 Intramural Research Program of the NIH, National Institute on Aging National Institutes of Health HHSN268200782096C Hong Kong Research Grant Council HKU 768610M Bone Health Fund of HKU Foundation KC Wong Education Foundation Small Project Funding 201007176237 Matching Grant CRCG Grant Osteoporosis and Endocrine Research Fund Genomics Strategic Research Theme of The University of Hong Kong Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810 Erasmus Medical Center and Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission (DG XII) Municipality of Rotterdam German Bundesministerium fur Forschung und Technology 01 AK 803 A-H 01 IG 07015

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Identification of high-risk groups for complication after arthroplasty: predictive value of patient’s related risk factors

Abstract Background Total joint arthroplasty (TJA) benefit patients with osteoarthritis (OA) and rheumatoid arthritis (RA). However, a specific approach to detect patients at higher risk of prosthetic joint infection (PJI) and mechanical complications is absent. The aim of this study is to identify groups at higher risk for infections and mechanical complications after TJA in patients with RA and OA based on their most significant predictors. Methods This is a hospital-based cohort study with 1150 recipients of TJA. Risk factors and comorbidities were assessed prior to the index surgery. Multivariate logistic and hazard regression were used to determine the relationship between risk factors and occurrence of complications after TJA. Odds ratios (OR), hazard ratios (HR), 95% confidence intervals (CI), and comparison between areas under the curve (AUC) using DeLong’s method are presented. Results Complications were more frequent in subjects with RA, use of corticosteroids, and previous comorbidities: respiratory disease, infections, diabetes, anemia, mental and musculoskeletal comorbidities than in subjects without these risk factors, and these factors were predictors of infections and mechanical complications (P < 0.05). A model including these factors was superior to a model with only type of joint disease (OA/RA) or age and gender to detect infections or mechanical complications after TJA (P < 0.05 for difference between models). Complication risk proportionally increased with the presence of two or more comorbidities (P < 0.001). Conclusions There are two groups at higher risk for infections after TJA: patients with OA with at least two risk factors and patients with RA, who usually present at least one of the risk factors for infection

Association of lumbar disc degeneration with osteoporotic fractures; the Rotterdam study and meta-analysis from systematic review

Objective: To investigate the relation between lumbar disc degeneration (LDD) and all type of osteoporotic (OP) fractures including vertebral. Methods: This study is part of the Rotterdam study, a large prospective population-based cohort study among men and women aged 55 years and over. In 2819 participants spine radiographs were scored for LDD (osteophytes and disc space narrowing (DSN)) from L1 till Si, using the Lane atlas. Osteoporotic (OP) fracture data were collected and verified by specialists during 12.8 years. We considered two types of vertebral fractures (VFx): Clinical VFx (symptomatic fractures recorded by medical practit Results: In a total of 2385 participants, during 12.8 years follow-up, 558 suffered an OP-fracture. Subjects with LDD had an increased OP fracture risk compared to subjects without LDD (HR: 129, CI: 1.04-1.60). LDD-cases have between 03 and 0.72 standard deviations more BMD than non-cases in all analyzed regions including total body BMD and skull BMD (P < 0.001). Only males with LDD had increased risk for OP-fractures compared to males without LDD (adjusted-HR: 1.80, 95%CI 1.20-2.70, P = 0.005). Conclusions: Male subjects with LDD have a higher osteoporotic fracture risk, in spite of systemically higher BMD. (C) 2013 Elsevier Inc. All rights reserved

Association of lumbar disc degeneration with osteoporotic fractures; the Rotterdam study and meta-analysis from systematic review

Objective: To investigate the relation between lumbar disc degeneration (LDD) and all type of osteoporotic (OP) fractures including vertebral. Methods: This study is part of the Rotterdam study, a large prospective population-based cohort study among men and women aged 55 years and over. In 2819 participants spine radiographs were scored for LDD (osteophytes and disc space narrowing (DSN)) from L1 till Si, using the Lane atlas. Osteoporotic (OP) fracture data were collected and verified by specialists during 12.8 years. We considered two types of vertebral fractures (VFx): Clinical VFx (symptomatic fractures recorded by medical practit Results: In a total of 2385 participants, during 12.8 years follow-up, 558 suffered an OP-fracture. Subjects with LDD had an increased OP fracture risk compared to subjects without LDD (HR: 129, CI: 1.04-1.60). LDD-cases have between 03 and 0.72 standard deviations more BMD than non-cases in all analyzed regions including total body BMD and skull BMD (P < 0.001). Only males with LDD had increased risk for OP-fractures compared to males without LDD (adjusted-HR: 1.80, 95%CI 1.20-2.70, P = 0.005). Conclusions: Male subjects with LDD have a higher osteoporotic fracture risk, in spite of systemically higher BMD. (C) 2013 Elsevier Inc. All rights reserved